Journal article
Genetic variation across RNA metabolism and cell death gene networks is implicated in the semantic variant of primary progressive aphasia
Scientific reports, Vol.9(1), 10854
07/26/2019
DOI: 10.1038/s41598-019-46415-1
PMCID: PMC6659677
PMID: 31350420
Abstract
The semantic variant of primary progressive aphasia (svPPA) is a clinical syndrome characterized by neurodegeneration and progressive loss of semantic knowledge. Unlike many other forms of frontotemporal lobar degeneration (FTLD), svPPA has a highly consistent underlying pathology composed of TDP-43 (a regulator of RNA and DNA transcription metabolism). Previous genetic studies of svPPA are limited by small sample sizes and a paucity of common risk variants. Despite this, svPPA's relatively homogenous clinicopathologic phenotype makes it an ideal investigative model to examine genetic processes that may drive neurodegenerative disease. In this study, we used GWAS metadata, tissue samples from pathologically confirmed frontotemporal lobar degeneration, and in silico techniques to identify and characterize protein interaction networks associated with svPPA risk. We identified 64 svPPA risk genes that interact at the protein level. The protein pathways represented in this svPPA gene network are critical regulators of RNA metabolism and cell death, such as SMAD proteins and NOTCH1. Many of the genes in this network are involved in TDP-43 metabolism. Contrary to the conventional notion that svPPA is a clinical syndrome with few genetic risk factors, our analyses show that svPPA risk is complex and polygenic in nature. Risk for svPPA is likely driven by multiple common variants in genes interacting with TDP-43, along with cell death,x` working in combination to promote neurodegeneration.
Details
- Title: Subtitle
- Genetic variation across RNA metabolism and cell death gene networks is implicated in the semantic variant of primary progressive aphasia
- Creators
- Luke W Bonham - University Memory and Aging CenterNatasha Z R Steele - University Memory and Aging CenterCeleste M Karch - Washington University in St. LouisIris Broce - University of California, San FranciscoEthan G Geier - University Memory and Aging CenterNatalie L Wen - Washington University in St. LouisParastoo Momeni - Texas Tech University Health Sciences CenterJohn Hardy - University College LondonZachary A Miller - University Memory and Aging CenterMaria Luisa Gorno-Tempini - University of California, San FranciscoChristopher P Hess - University of California, San FranciscoPatrick Lewis - University College LondonBruce L Miller - University of California, San FranciscoWilliam W Seeley - University of California, San FranciscoClaudia Manzoni - University College LondonRahul S Desikan - University of California, San FranciscoSergio E Baranzini - University of California, San FranciscoRaffaele Ferrari - University College LondonJennifer S Yokoyama - University Memory and Aging CenterInternational FTD-Genomics Consortium (IFGC)Timothy Griffiths (Contributor) - Psychological and Brain Sciences
- Resource Type
- Journal article
- Publication Details
- Scientific reports, Vol.9(1), 10854
- DOI
- 10.1038/s41598-019-46415-1
- PMID
- 31350420
- PMCID
- PMC6659677
- ISSN
- 2045-2322
- eISSN
- 2045-2322
- Grant note
- U01 DA041148 / NIDA NIH HHS U01 DA041174 / NIDA NIH HHS K24 DC015544 / NIDCD NIH HHS K01 AG046374 / NIA NIH HHS K01 AG049152 / NIA NIH HHS P01 AG019724 / NIA NIH HHS U24 DA041123 / NIDA NIH HHS U01 DA041022 / NIDA NIH HHS MC_U123160651 / Medical Research Council R01 NS050915 / NINDS NIH HHS U01 DA051039 / NIDA NIH HHS P50 AG023501 / NIA NIH HHS R01 NS100440 / NINDS NIH HHS U01 DA050989 / NIDA NIH HHS P30 AG062422 / NIA NIH HHS MR/N026004/1 / Medical Research Council U01 DA041093 / NIDA NIH HHS G0301152 / Medical Research Council U01 DA041025 / NIDA NIH HHS R56 NS050915 / NINDS NIH HHS U01 AG052943 / NIA NIH HHS MR/L010933/1 / Medical Research Council U01 DA041106 / NIDA NIH HHS MC_UU_00024/1 / Medical Research Council
- Language
- English
- Date published
- 07/26/2019
- Academic Unit
- Psychological and Brain Sciences
- Record Identifier
- 9984627192302771
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